Depot forms can be administered in different ways, for example, orally, parenterally, ocularly, pulmonally or by sprinkling in wounds. Depot forms, also referred to as parenteral slow-release forms, appropriate for parenteral administration are of particular interest.
Parenteral slow-release forms can be formulated as microparticles, implants and fibers. Microparticles are of special interest, since, because of their limited dimensions, they can be suspended in an appropriate medium and administered comparatively painlessly by means of a syringe via an injection needle with limited diameter.
Such formulations are of interest for all pharmacologically active substances if long-persisting, uniform systemic or local active ingredient concentrations are desired. They are particularly advantageous for active ingredients that are destroyed or insufficiently resorbed during oral administration and can only be applied parenterally. This is the case, for example, in pharmacologically active peptides, like peptide hormones or proteins.
Of special interest are interleukins (IL-1 to IL-15), interferons (IFN), neurotrophins (NT-1 to NT-3), colony-stimulating factors (CSF), epidermal growth factors (EGF), neuronal growth factors, prolactin, luteinizing-hormone-releasing hormone (LH-RH), insulin, somatostatin, glucagon, gastrin, pentagastrin, urogastrone, calcitonin, secretin, enkephalins, endorphins, angiotensins, renin, bradykinin, tyrocidine, gramicidins, erythropoetin (EPO), angiopeptin, hirudin, oxytocin, vasopressin, calcitonin-gene-related peptide (CGRP), brain-derived growth factors (BDGF), their synthetic analogs and modifications, as well as their pharmacologically active fragments.
Generally the most constant possible active ingredient release over the entire release period is aimed for in parenteral slow-release formulations. Release of the active ingredients from depot forms made of biodegradable matrix polymers is dictated by their diffusion rate in the polymer and their degradation rate. To avoid accumulation of the matrix polymer during successive application this should be degraded as fully as possible after completion of active ingredient release.
Biodegradable matrix polymers for active ingredient embedding have already been described in 1973 in U.S. Pat. No. 3,773,919. Polymers from hydroxycarboxylic acids, especially lactic and/or glycolic acid were proposed. Polymers from lactic and/or glycolic acid are hydrolyzed in the body to lactic and/or glycolic acid, which are further metabolized to CO.sub.2 and water and are therefore particularly usable in the production of parenteral slow-release forms.
Depot forms from polylactic acid (PLA) or polylactic-glycolic acid (PLGA), especially microparticles, generally exhibit a multiphase release trend and initially display a sharply increased release because of active ingredient present on the surface. This is followed by a phase of sharply reduced or nonexistent release, especially in peptide active ingredients, which is then followed by later active ingredient liberation supported by polymer mass degradation. Polymer residues are still present at the time of completion of active ingredient liberation.
EP 0 058 481 B1 describes the use of a mixture of PLGA having different molecular weights. Liberation is supposed to be linearized by this and the degradation rate adjusted to the liberation period. Use of such polymer mixtures, however, imposes high requirements on the hydrolysis stability of the active ingredient and they are not suitable for the production of microparticles.
EP 0 407 617 describes a biocompatible polyester with increased hydrolysis rate consisting of saccharides bonded to PLA or PLGA. The polyesters are proposed as matrix material for depot forms but a corresponding practical example is not included.
If depot forms can be produced with these polymers, it does appear possible to develop more rapidly degradable depot forms, but the problem of nonuniform active ingredient liberation and especially the problem of the initial burst effect persist.
DE 34 30 852 A1 describes esters from polyols and poly- or copolylactic acid, which are also proposed as matrix polymers for depot forms. Example 26 entails in-vitro liberation of washed microparticles containing bromocryptin mesylate produced by spray drying. Despite washout of the active ingredient adhering to the microparticle surface, after 24 hours 62% of the active ingredient load had already been liberated.
Slow-release forms with sufficiently high active ingredient load often cannot be produced with the known matrix polymers. However, high active ingredient load of slow-release forms is desirable, since the amount to be administered in each case is limited by its intramuscular or subcutaneous administration and the long application intervals sought for slow-release forms often can only be achieved in this manner.
However, an increase in active ingredient load generally leads to insufficient retardation, depending on the physicochemical properties of the active ingredient. Hydrophilic active ingredients in particular, for example, those present in dissociated form under physiological conditions, therefore cannot be used in the required high concentration in the known matrix polymers and exhibit nonuniform active ingredient release, especially an increased initial active ingredient release (burst effect).
It was therefore the task of the present invention to offer matrix polymers that do not exhibit the described problems. The matrix polymers were to permit high active ingredient load and liberate the active ingredients in delayed fashion without fluctuations. The rate and overall duration of polymer degradation has to be adjusted to the rate and duration of active ingredient release so that after the end of release another dose of the depot form can be administered without running the risk of accumulation of the matrix polymer in the body.